The present invention relates to a general process for preparing aromatic aldehydes and alcohols. More particularly, it relates to the preparation of benzaldehyde and benzilic alcohol, and of derivatives thereof, like for instance 3,4,5-trimethoxybenzaldehyde and 3,4,5-trimethoxy benzyl alcohol.
The industrial utility of benzaldehyde in the manufacture of colouring and aromatizing substances as intermediate in the production of cinnamic and mandelic acid and as solvent is well-known, while benzyl alcohol is used, for instance, as bacteriostatic and solvent for gelatine, casein and cellulose acetate. In particular, 3,4,5-trimethoxybenzaldehyde is a valuable intermediate in the synthesis of many pharmaceutical products, especially in the production of 2,4-diammino-5-(3,4,5-trimethoxy)benzyl-pyrimidine (trimethoprim).
In view of the importance, for the pharmaceutical industry, of the synthesis of 3,4,5-trimethoxybenzaldehyde and of the well-known difficulties and disadvantages (which will be illustrated in detail hereinafter) carried by the traditional processes of synthesis of this intermediate, the process for the production of aromatic alcohols and aldehydes of the present invention will be particularly described with reference to the synthesis of the benzaldehyde derivative. It is to be understood, as it is illustrated in the examples and evident for anyone skilled in organic synthesis, that the present process has a general character and can be used, choosing the suitable raw material, for the preparation of other aromatic aldehydes and alcohols.
The two industrial processes that are more widely used for producing 3,4,5-trimethoxybenzaldehyde are both unsatisfactory, both because of the very high cost of the desired product and of the poor yields of the reactions involved in these processes.
The first process is based on the Rosemund reduction of 3,4,5-trimethoxy benzoic acid chloride and the second one consists in the bromuration of vanilline, followed by methylation of the hydroxyl group in position 4 in respect to the carbonyl and in the simultaneous substitution of the bromine atom with a methoxyl group.
This second process is described by patent U.S. Pat. No. 3,855,306. The process based on the catalytic hydrogenation of 3,4,5-trimethoxybenzoic acid chloride, following the method of Rosemund, in aromatic solvents containing a poison of the catalyst, was studied by several authors. But no one of them overcame the very heavy inconveniences (from the industrial point of view) connected with the yields, which are neither very high nor constant (50-80% of the theory).
Other processes which have been described are transformations of 3,4,5-trimethoxybenzoic acid chloride in 3,4,5-trimethoxybenzaldehyde with yields of 64-83% of distilled product by means of a variation of the Rosemund process, that is in presence of sodium acetate as a hydrogen ion acceptor. In this process the reduction of 3,4,5-trimethoxybenzoic acid chloride must be carried out in the presence of a disactivant (solvent toluene) like sulphur-quinoline and sodium acetate on palladiate charcoal (5%) during many hours at room temperature and 2 hours at 50.degree. C. and 50 psi of hydrogen. In several experiments carried out in the above described conditions, a product of 84% purity with a yield of 72-74% has been obtained.
Moreover, it is pointed out that, whereas 3,4,5-methoxybenzoic acid, which is the raw material for the preparation of the chloride, is easily found on the market at a reasonable cost, the chloride, obtained from the acid by treatment with thionyl chloride is not easily prepared on an industrial scale, especially because the subsequent Rosemund hydrogenation requires a product of high grade of purity. In fact, on the market the chloride of 3,4,5-trimethoxybenzoic acid has a price which is two times higher than the one for the starting acid.
In conclusion, the 3,4,5-trimethoxy-benzaldehyde prepared by the Rosemund more or less modified method has by far, too high a price for a starting material for the production of drugs, which are indispensable for large widespread consumption.
The process described in the patent U.S. Pat. No. 3,855,306 comprehend the prepartion of 5-bromovanillin starting from vanillin. The cost of vanillin is already higher than that for 3,4,5-trimethoxybenzoic acid; however the reaction proceeds easily and with high yields (about 98% of theoretical).
From the 5-bromo derivative, by treating it with KOH and methanol, the 3,4,5-trimethoxybenzaldehyde is obtained. The yields however, of that step are not economically acceptable. There are no better results where the methylation of 5-bromo vanillin and substituting afterwards the bromine atom with the methoxy group are carried out separately.
Using the method which utilize vanillin as a starting material, we are unable to obtain 3,4,5-trimethoxy benzaldehyde at an acceptable cost.
The reduction operations which leads from the 3,4,5-trimethoxy benzoic acid to the corresponding aldehyde directly by means of metallic hydrides give an even more costly product. Experiments carried out with the aim to directly introduce the carbonyl group in the pyrogallol or in the trimethoxybenzene failed, since the carbonyl group does not enter in the requested position.
It is well known in organic chemistry how possible it is, also on an industrial scale, to produce aldehydes from alcohols by means of oxidations with suitable oxidative agents. If this method is applied to the 3,4,5-trimethoxybenzaldehyde for big productions, the chief problem is obtaining 3,4,5-trimethoxybenzyl alcohol at low cost.